Peroxisome proliferator-activated receptor-B/d (PPARB/d)-null mice exhibit enhanced tumor formation in both skin and colon and ligand activation of PPARB/d inhibits tumor multiplicity in both skin and colon. The mechanisms underlying the inhibition of tumorigenicity by a PPARB/d ligand is likely due to the induction of terminal differentiation and increased apoptosis that requires PPARB/d since these effects are not found in similarly treated PPARB/d-null mice. Additionally, PPARB/d-dependent modulation of ubiquitin-mediated regulation of critical cell proliferation/apoptotic pathways could also be a central mechanism underlying the inhibition of tumorigenicity by PPARB/d ligands. The central hypothesis of this proposal is that the PPARB/d modulates the molecular events that lead to skin carcinogenesis from genetic and chemical factors. Inhibition of skin carcinogenesis by cyclooxygenase (COX) inhibitors is 1 approach that is known to inhibit skin tumorigenicity, but is not 100% effective. We have recently demonstrated that inhibition of chemically-induced skin cancer by COX inhibition is independent of PPARB/d. Additionally, others have recently shown that inhibition of cell proliferation by ligand activation of PPARB/d can be greatly enhanced when coupled with inhibition of COX. The first specific aim is to test the hypothesis that combining ligand activation of PPARB/d with inhibition of COX activity will inhibit skin carcinogenesis with greater efficacy than either treatment by itself. This will be examined by 2-stage chemical carcinogen testing in wild-type and PPARB-null mice, in the presence or absence of COX inhibitors and/or a specific PPARB/d ligand. The inhibitory action of this combined approach will be examined during tumor initiation and progression, and in mice with pre-existing tumors. The second specific aim will test the hypothesis that PPAR?/d-dependent up-regulation of ubiquitin C expression will attenuate skin carcinogenesis. Analysis of keratinocyte-specific ubiquitin C transgenic will determine if PPARB/d-dependent modulation of ubiquitin expression can ameliorate the enhanced tumorigenicity observed in the absence of PPARB/d-dependent ubiquitin C expression, and identify critical PPARB/d-mediated, ubiquitin-dependent pathways that lead to skin cancer. Collectively, these studies will determine if combining ligand activation of PPARB/d with COX inhibition has greater efficacy at inhibiting tumor growth and/or tumor multiplicity than either single treatment and elucidate the mechanisms of PPARB/d-mediated inhibition of chemically-induced skin carcinogenesis. Results from these studies will provide useful novel targets for chemoprevention or chemotherapy that will likely lead to translational research in humans. Lay relevance: More than 1 million cases of skin cancer are diagnosed annually within the United States. The annual cost of all cancers exceeds billions of dollars. Risk factors for skin cancer include UV light and exposure to environmental chemical carcinogens. Results from these studies will determine if a combinational approach can more effectively inhibit skin cancer, determine the critical stage of skin carcinogenesis where PPARB-dependent regulation is significant, and provide new molecular targets to inhibit/prevent chemically-induced skin cancer.